This invention relates to a radioiodinated aromatic amine attached to dihydropyridine carriers that show tissue specificity and are potentially useful as imaging agents. Although this radiopharmaceutical was developed for application as a brain imaging agent, it also exhibits specificity in other tissues, most notably the heart.
The ability to measure cerebral blood flow is useful in the gathering of clinical information for the identification and evaluation of brain lesions. The technology recently developed to make such measurements involves the use of a radiopharmaceutical agent in conjunction with single photon emission computerized tomography (SPECT). One approach in the development of an appropriate radiopharmaceutical agent is to first select a suitable radioisotope and then attach that radioisotope to a carrier that can cross the intact blood-brain barrier. The complexity of the problem becomes apparent when one considers the many radioisotopes that could possibly be chosen such as technetium, fluorine, thallium, and iodine to name a few, as well as possible carriers such as amphetamines, barbiturates, or other compounds that exhibit central nervous system activity.
The most recent work in the area of brain imaging using SPECT has involved the use of the radioisotope iodine-123 which has excellent radionuclidic and chemical properties for use in diagnostic radiopharmaceuticals. The emission of abundant (84%) 159 keV gamma photons allows the use of Anger-type cameras which are available in all nuclear medicine clinics. This radionuclide, iodine-123, has been used in conjunction with fatty acids, human serum albumin and triglycerides to develop radiopharmaceutical agents.
Experimental work has continued to arrive at a suitable carrier for transporting the radionuclide. One consideration, and perhaps the most important, is the ability of a molecule to pass the blood-brain barrier. This ability is a function of its partition coefficient between lipid and water. Lypophilic organic compounds cross the intact blood-brain barrier and mimic regional blood flow which is a necessary characteristic for the radiopharmaceutical agents under consideration. One known carrier is in the form of an amphetamine which has been reported and shows good retention in the brain. Previous work has also involved an attempt at using radiolabeled barbiturates. Although barbiturates exhibited good brain uptake, the transport was reversible with the carrier leaving the brain as rapidly as it entered resulting in washout and rapid clearance of the isotope from the brain. There was also exhibited a low brain:blood ratio resulting in high background radioactivity. The barbiturates also have the disadvantage, which can be attributed to the amphetamines as well, of having an addictive effect on the central nervous system. Recently a dihydropyridine derivative of a quaternary salt that can be delivered to the brain was reported by Bodor et al. The derivative was developed for chemotherapeutic treatment of brain disease, but offers possible applications in brain imaging technology with further development. In view of the problems in this area there is a need for an improved radiopharmaceutical agent that can enter the brain and be used in conjunction with known imaging methods to detect certain occurrences within the brain.